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PAD prevalent among patients with diabetes, metabolic syndrome
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While knowledge of peripheral arterial disease has progressed, much is needed still in the way of comparator trials and efficacy of new diagnostic approaches.
Peripheral artery disease – also referred to as peripheral vascular disease or PVD – affects > 9 million Americans and more than 10 million in Europe, according to Alan T. Hirsch, MD, director of the vascular medicine program at the Minneapolis Heart Institute at Abbott Northwestern Hospital. “PAD is one of the most prevalent, morbid and mortal CVDs,” he said. “The cost of PAD is as high and likely higher than any other CVD.”
PAD is also a marker for atherosclerosis and a predictor of death, MI or stroke. Add diabetes into the mix and, “patients with diabetes are at the highest risk,” Hirsch said.
Reena L. Pande, MD, a fellow in CV medicine at Brigham & Women’s Hospital, said available literature shows that 52% of people with PAD demonstrate features of metabolic syndrome. A direct measure of insulin resistance — homeostasis model of insulin resistance — was linked to PAD in NHANES, and Pande said it is no surprise that inflammation, which is linked with insulin resistance, is also related to PAD. The Edinburgh Artery Study shows that patients with diabetes and glucose intolerance have a higher risk for PAD.
“Diabetes increases the risk of amputation and death in patients with PAD,” Pande added.
She said that whether improving insulin resistance would improve outcomes in PAD has not yet been proven, although reducing inflammation with statins has demonstrated a reduction in incidence of claudication, improvement in walking distance and an increase in more pain-free walking.
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Courtesy of: Scott Reiff, MD |
“Limitations in nutrient uptake into the exercising skeletal muscle, as might happen in insulin-resistant states, may well impair function and exercise ability in patients with PAD. Theoretically it makes sense that if we can improve insulin sensitivity at the level of the skeletal muscle in the lower extremity, we may be able to get patients walking further and walking with less discomfort. But that data are not yet known,” Pande said.
Biomarkers and diagnostics
In other areas of PAD research, it is still not yet known which biomarkers are specific to PAD. There are novel biomarkers for CV risk — like CRP or endothelial progenitor cells — but none that are specific to PAD.
PAD is diagnosed by vascular examinations including the office-based ankle brachial index (ABI), but John Cooke, MD, PhD, professor of medicine at Stanford University, said that routine screening with ABI is not done and at least two-thirds of Americans with PAD are undiagnosed.
“The diagnosis of PAD is not being made,” Cooke said. “Whereas ABI is the current gold standard in the office, it is not being utilized. If we had a blood test for PAD, there would be much higher rates of screening.”
Cooke said biomarker research is at an early stage, but researchers are hoping to find biomarkers that will lead to better diagnostic tests, better pathophysiological understanding and potential therapeutic targets.
Research into protein biomarkers has shown promise. Cooke said he and his colleagues are working on a bead technique to equalize proteins in plasma to have a better chance of finding the right flags for PAD.
“We’ve got a long way to go as it’s very early in the field right now,” Cooke said. “What we’re looking for is a panel that reflects multiple processes that are occurring locally in skeletal muscle, which are circulating systemically.”
In other areas of PAD diagnostics, Christopher M. Kramer, MD, professor of medicine and radiology, director of the CV imaging center at the University of Virginia Health System, and colleagues are developing new MRI-based methods for clinical trials in PAD.
“Instead of just making measurements at peak exercise, we’re now able to measure perfusion reserve, the ratio of blood flow in the calf at peak exercise over that at baseline, and this may be a more accurate assessment of PAD,” Kramer said.
Kramer said these methods use a pedal ergometer attached to the MRI machine that allows patients to exercise their calf while in the scanner. The researchers are addressing the issue of gadolinium intolerance in patients with severe renal insufficiency by developing techniques that do not require contrast but are still MRI-based.
Results of a study using multi-modality MRI, including imaging of the vessel wall and atherosclerotic plaque as well as the blood flow measures in patients with PAD, is scheduled to appear in the August issue of the Journal of the American College of Cardiology, Kramer said.
CLEVER trial enrolling patients
Hirsch said there is a “critical national” need for clinical trials that determine the most effective and lowest risk for treatment of PAD. Hirsch said the largest and most relevant multicenter trial right now is the CLEVER study, sponsored by the National Heart, Lung, and Blood Institute of the NIH and led by principal investigator Timothy Murphy, MD, the medical director of the Vascular Disease Research Center at Brown University.
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Hirsch said that clinicians caring for patients with PAD, including all vascular specialists, should enroll qualifying patients (defined as patients with aorto-iliac PAD and claudication, and if applicable, diabetes, into the CLEVER trial. The trial will compare the efficacy, risk and health economic effect of aorto-iliac revascularization with a six-month program of supervised exercise vs. home exercise with use of cilostazol (Pletal, Otsuka Pharmaceuticals) in the treatment of claudication. Hirsch said recruitment has been slow since the trial was initiated in 2007.
“In contrast to the major advances that have been achieved for patients with CAD, infectious diseases, orthopedic conditions or cancer, in which all physicians … seem committed to helping advance their field via unambiguous support of clinical research, vascular specialists seem amazingly unable to commit themselves to randomize patients in their own major multicenter clinical research trials,” Hirsch said. “This is the most challenging clinical study of scores that we have completed in PAD patients. If you live in a city that has a CLEVER investigator and you have a patient with aorto-iliac PAD and claudication, we would like your help.”
Interested physicians can visit the trial’s website for a contact phone number and more information (http://www.lifespan.org/services/clintrials/vdrc/studies/clever/).
“We need PAD trials that are uniquely different from everything that has happened before. Such trials must be multicenter, including all relevant treatment strategies,” Hirsh said. “One of the things that strikes me is how much our basic physiologic PAD knowledge base has been enhanced,” he said. “But, I do worry that we may not have transferred even a small fraction of this knowledge to the bedside. We need every clinician’s support for the CLEVER study.” – by Judith Rusk
For more information:
- Peripheral vascular disease – improving diagnosis and function. Symposia. Presented at: American Diabetes 69th Scientific Sessions; June 5-9, 2009; New Orleans.